Project Summary/Abstract Humans each harbor a complex microbiome with the genetic potential to produce a vast array of natural products. Recent sequencing data suggests that these microbiome communities are critical for maintaining our health. Shifts in microbiome communities have been correlated to a number of diseases, yet we know remarkably little about the role of natural products in maintaining these communities. My group?s long-term goal is to define metabolite mediated relationships between members of the pulmonary microbiota of cystic fibrosis patients and elucidate their functional role in community dynamics. We hypothesize that the constituents of the microbiome interact using natural products and that a convergence of these chemical signals determines community structure. The overall objective of this proposal is to develop and apply modern mass spectrometry based workflows in combination with traditional and emerging chemical, molecular, and biochemical approaches to investigate the role of small molecules within microbiome communities. Over the next five years, we will chemically characterize understudied microbes, 2) elucidate how microbial community structure affects metabolic output, and 3) understand how exogenous pressures (i.e. treatment, host metabolites, etc.) shape microbiome structure and function. This information will then be incorporated into a model network of microbiome interactions. The propose research is significant because it will provide the research community with a fundamental understanding of how microbiome derived compounds impact the structure and function of the microbiome, especially in regards to treatment. While our work focuses on the CF pulmonary microbiota, the methods and approaches we develop are broadly applicable to any microbiome.